1. Field of the Invention
The present invention generally relates to methods and compositions to alleviate eye diseases and, more specifically, to improved methods and compositions for the treatment of cataracts and macular degeneration.
2. Description of the Related Art
Macular degeneration associated with aging and drusen is an extremely significant concern, and is now a major cause of blindness in the United States for individuals over 65 years of age. Just at the period of time when the eyes are a most important sense, and reading and watching television are often the most enjoyable avenues of entertainment, this disease robs the elderly patient of such possibilities.
The crystalline lens of the eye has only one disease state that we are aware of, and that is cataract. The lens loses its clarity as it becomes opacified, and vision is disturbed depending on the degree of opacification. There are different etiologies for cataracts such as a congenital lesion or trauma, which are well recognized. It is also known that some medicines such as cortisone-type preparations and glaucoma medications can cause cataracts, as can inborn metabolic errors such as galactosemia. These, however, are relatively uncommon in comparison to the common aging cataract, which shows an increase in frequency directly correlated with age.
The exact incidence of cataracts in the general population is difficult to determine because it depends on one's definition of a cataract. If defined as simply a lens opacity, then obviously the incidence is much higher than when defined as a lens opacity that significantly impacts vision. The pathogenesis of age-related cataracts and macular degeneration is incompletely understood.
The accumulation of drusen and lipofuscin and the loss of retinal pigment, hallmarks of macular degeneration, appear to be a consequence of the accumulation of biomolecular derivatives of those bioactive molecules involved in photoreception and signal processing, and normally detoxified, processed, and exported from the RPE (retinal pigment epithelium). While the importance of controlling the accumulation of lipofuscin and its dominant component A2E, N-retinylidene-N-retinylethanolamine (Sparrow, 2001), which is responsible for converts visible-wavelength radiation into toxic ROSs (reactive oxygen species), no means for accomplishing this has been proposed and so the best means currently available for limiting the damage is by reducing the amount of radiation available to the lipofuscin. There also is no effective treatment to date for the resulting biodegeneration, except laser photocoagulation in patients who develop abnormal vessels under the retina, i.e., subretinal neovascularization. The treatable group is a distinct minority of a much larger group. Individuals so afflicted can anticipate either a progressive deterioration or at times relatively static course, but no spontaneous improvement, since the basic architecture of the retina is destroyed. Occasionally, there may be variations in vision which seem to show improvement depending on such things as lighting in the room and potential resolution of fluid underneath the retina. The important point, however, is that when this sensitive neurological tissue is damaged, that damage is permanent.
In 1981, Spector et al. stated that there still remained questions concerning the mechanism and agents involved with massive oxidation of the lens tissue and its relationship to cataract development (Spector et al. 1981). They also noted that glutathione (GSH) can act as a reducing agent and free radical trapper. Glutathione peroxidase (GSHPx) and catalase are present to metabolize H2O2. While superoxide dismutase (SOD) can detoxify O2, light can photochemically induce oxidation. However, Spector et al. believe that the actual roles of light and/or metabolically-generated oxidized components are unclear as to causing the observed oxidation products.
In 1987, Machlin et al. reported that there was some evidence that free radical damage contributed to the etiology of some diseases, including cataract (Machlin et al. 1987). They indicated that defenses against such free radical damage included Vitamin E, Vitamin C, beta carotene, zinc, iron, copper, manganese, and selenium.
In 1988, Jacques et al. reported that it is commonly believed that oxidative mechanisms are causally linked to, not simply associated with, cataract formation. According to Jacques et al. evidence suggests that GSHPx and SOD decrease with increasing degree of cataract.
Jacques et al. further reported that Vitamin E is believed to be a determinant of cataract formation and can act synergistically with GSHPx to prevent oxidative damage. They point out the possibility that Vitamin C may have a role in cataract formation and might influence GSHPx through its ability to regenerate Vitamin E.
Dietary supplements are taken for a variety of reasons including the improvement of vision or prophylaxis of vision loss. An example of a set of dietary supplements useful in promoting healthy eyes are the ICAPS® Dietary Supplements (Alcon Laboratories, Inc., Fort Worth, Tex.). Dietary supplements are generally in the form of powders, tablets, capsules or gel-caps and comprise a variety of vitamins, minerals, and herbal or other organic constituents. Some dietary supplements are formulated with beadlets.
Beadlets contain dietary substances and are generally small spheroids of less than about a millimeter in diameter. There are a variety of functions and purposes of beadlets. For example, beadlets may provide for the separate containment of ingredients within the dietary supplement to improve the stability of the entrapped ingredients.
Various beadlet compositions are known and can be obtained from a number of food ingredient or pharmaceutical manufacturers including H. Reisman Corp. (Orange, N.J.), BASF (Mount Olive, N.J.), BioDar (Israel), and Hoffinann-LaRoche (Nutley, N.J.). Particular beadlet compositions have been the subject of several patents including U.S. Pat. No. 4,254,100 (Keller et al.) and 3,998,753 (Antoshkiw et al.). Numerous methods of beadlet manufacture have been disclosed, e.g. in U.S. Pat. Nos. 4,670,247; 3,998,753 and published U.S. application No. 20030064133.
Current beadlet compositions used in dietary supplements generally are restricted to the use of inert ingredients and excipients complementary to a single nutritional compound. In other instances, when molecules of the same class are refined from a particular source, for example a major component with a minor related constituent, and both compounds produce parallel effects, such molecules may not necessarily be isolated but mixed together in a beadlet. These may be considered pseudo-single-component beadlets, and there are examples in the market place, e.g., Lutrinol® and FloraGLO® beadlets, which are a combination of lutein and zeaxanthin as formulated in Retoxil® Dietary Supplements. Examples of ingredients benefiting from beadlet confinement have included natural vitamins such as Vitamins A, D, E, and K; xanthophylls such as lutein, zeaxanthin, canthaxanthin, and astaxanthin; and carotenes, such as beta-carotene, lycopene, and retinol.
Recent data has suggested that the inclusion of xanthophylls and other carotenoids in dietary supplements may provide superior dietary supplements useful in enhancing the health of the eye. Studies have shown the selective uptake of the carotenoids, zeaxanthin and lutein, by the macula of the eye (Bernstein et al. 1997; Hammond et al. 1997; and Handelman et al. 1991). This earlier work revealed the presence of both lutein and its positional isomer, [R,R]-zeaxanthin. More recently, a second isomer of zeaxanthin has been found in the macula, the diastereomer meso-zeaxanthin, the [R,S] isomer of zeaxanthin (Bone & Landrum). These and related observations suggest both are essential for improved ocular health and protection of the macula.
Xanthophylls are effective phytochemical antioxidants and are known to localize in the macula of the retina. It has been suggested that the particular xanthophylls, zeaxanthin and its isomer lutein, may be beneficial in improving the health of the macula and the clarity of the lens. These molecules may function in a number of ways to protect the eye from high intensity radiation or other insults. It has been suggested that foveal proteins bind the xanthophylls, localize and concentrate xanthophylls within the fovea. Since xanthophylls are capable of absorbing photoexcitative radiation of short visible wavelength, they also may shield the light-sensitive, underlying cells of the neural retina and RPE. Such cells are responsible for high-definition vision and have been shown by epidemiological studies to be adversely affected by exposure to high intensity radiation or even chronic exposure to visible wavelength radiation. The carotenoids are believed to complement the activity of these cells, and also to protect them against photochemical insult. See, e.g., Snodderly (1995) and Seddon et al. (1994).
Studies also have shown that the portion of the retina associated with xanthophyll deposition undergoes one of the highest metabolic rates in the body (Berman 1991). The energy to sustain this metabolism is derived from oxidation. While the very lipophilic xanthophylls do not appear to undergo rapid turnover characteristic of water-soluble antioxidants (Hammond et al. 1997), continuous exchange of xanthophylls occurs in response to both environmental challenge and tissue environment, and their gradual depletion without nutritional replacement may portend tissue damage (Hammond et al. 1996a; Hammond et al. 1996b; and Seddon et al. 1994). The lack of rapid turnover also implicates the role of other synergistic antioxidants, vitamins C and E especially but also enzymatic antioxidants that are active in the redox cascade that passes the initial oxidative excitation to lower-energy and less damaging species.
The carotenes are conjugated C40 compounds that include beta carotene (a provitamin A precursor). The carotenes are deeply colored compounds and are found throughout the plant kingdom, e.g., in leafy vegetables such as spinach and kale, and brilliantly colored fruits such as melons and pineapple. While the carotenes are ubiquitous in the plant kingdom, they generally are not available biosynthetically in mammals. Since the carotenes are essential for normal mammalian health, mammals need to ingest various sources of the carotenes, e.g., fruits and vegetables. The absence of carotenoids from the diet, especially the carotene derivative, vitamin A, is known to be associated with degenerative eye diseases.